The aggregation of alpha-synuclein is believed to be a critical factor in the etiology of Parkinson's disease (PD). alpha-Synuclein is the major component of Lewy bodies and Lewy neurites, the intracellular inclusions that are a pathological hallmark of Parkinson's disease. There is a critical need for an effective treatment of Parkinson's disease, since current therapies are only partially effective in treating the symptoms. Through the proposed research we plan to develop inhibitors of alpha-Synuclein fibrillation, which could lead to new therapies to halt the disease progression. We recently discovered that dopamine and several related molecules not only inhibit the formation of alpha-Synuclein fibrils in vitro, but also break down existing a-synuclein fibrils formed in vitro. This unexpected observation raises several obvious questions, including: Could a decrease in L-DOPA or dopamine production or levels be a triggering factor in PD? Will dopamine and its analogs dissolve Lewy bodies? Can we find related compounds that would form the basis of a therapeutic intervention? What is the mechanism of dopamine inhibition of alpha-Synuclein fibrillation? Our goals in this proposal are: (1) To test the hypothesis that dopamine and its analogs bind specifically and tightly to an intermediate of alpha-Synuclein fibrillation, thus inhibiting fibril formation, and to investigate exactly how dopamine and related compounds prevent fibril formation. Knowing how DA prevents fibrillation of alpha-Synuclein should provide the basis for the design of inhibitors that will be potential drags for preventing alpha-synuclein fibrillation. (2) To determine if DA and its analogs also prevent fibril formation in vivo using both tissue sections and animal models. (3) To determine the essential parts of the dopamine structure for inhibition of alpha-Synuclein fibrillation, and to design new inhibitors of a-synuclein aggregation based on this knowledge. The results of the proposed research will provide leads for inhibitors of alpha-synuclein aggregation and lay the groundwork for potential therapeutic approaches. In the long-run this research could provide new strategies for the treatment of Parkinson's disease.